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Cell-assembled extracellular matrix (CAM) sheet production: Translation from using human to large animal cells.

ABSTRACT: We have created entirely biological tissue-engineered vascular grafts (TEVGs) using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts in vitro. A large animal TEVG would allow long-term pre-clinical studies in a clinically relevant setting (graft size and allogeneic setting). Therefore, canine, porcine, ovine, and human skin fibroblasts were compared for their ability to form CAM sheets. Serum sourcing greatly influenced CAM production in a species-dependent manner. Ovine cells produced the most homogenous and strongest animal CAM sheets but remained ?3-fold weaker than human sheets despite variations of serum, ascorbate, insulin, or growth factor supplementations. Key differences in cell growth dynamics, tissue development, and tissue architecture and composition were observed between human and ovine. This study demonstrates critical species-to-species differences in fibroblast behavior and how they pose a challenge when attempting to substitute animal cells for human cells during the development of tissue-engineered constructs that require long-term cultures.

SUBMITTER: Torres Y

PROVIDER: S-EPMC7887678 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Cell-assembled extracellular matrix (CAM) sheet production: Translation from using human to large animal cells.

Torres Yoann Y Gluais Maude M Da Silva Nicolas N Rey Sylvie S Grémare Agathe A Magnan Laure L Kawecki Fabien F L'Heureux Nicolas N

Journal of tissue engineering 20210101

We have created entirely biological tissue-engineered vascular grafts (TEVGs) using sheets of cell-assembled extracellular matrix (CAM) produced by human fibroblasts <i>in vitro</i>. A large animal TEVG would allow long-term pre-clinical studies in a clinically relevant setting (graft size and allogeneic setting). Therefore, canine, porcine, ovine, and human skin fibroblasts were compared for their ability to form CAM sheets. Serum sourcing greatly influenced CAM production in a species-dependen ...[more]

PMID: 33633827

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Project description:Effective cellularization is a key approach to prevent small-caliber (<4 mm) tissue-engineered vascular graft (TEVG) failure and maintain patency and contractility following implantation. To achieve this goal, however, improved biomimicking designs and/or relatively long production times (typically several months) are required. We previously reported on porcine carotid artery decellularization yielding biomechanically stable and cell supportive small-caliber (3-4 mm diameter, 5 cm long) arterial extracellular matrix (scaECM) vascular grafts. In this study, we aimed to study the scaECM graft patency in vivo and possibly improve that patency by graft pre-endothelialization with the recipient porcine autologous cells using our previously reported custom-designed dynamic perfusion bioreactor system. Decellularized scaECM vascular grafts were histologically characterized, their immunoreactivity studied in vitro, and their biocompatibility profile evaluated as a xenograft subcutaneous implantation in a mouse model. To study the scaECM cell support and remodeling ability, pig autologous endothelial and smooth muscle cells (SMCs) were seeded and dynamically cultivated within the scaECM lumen and externa/media, respectively. Finally, endothelialized-only scaECMs-hypothesized as a prerequisite for maintaining graft patency and controlling intimal hyperplasia-were transplanted as an interposition carotid artery graft in a porcine model. Graft patency was evaluated through angiography online and endpoint pathological assessment for up to 6 weeks. Our results demonstrate the scaECM-TEVG biocompatibility preserving a structurally and mechanically stable vascular wall not just following decellularization and recellularization but also after implantation. Using our dynamic perfusion bioreactor, we successfully demonstrated the ability of this TEVG to support in vitro recellularization and remodeling by primary autologous endothelial and SMCs, which were seeded on the lumen and the externa/media layers, respectively. Following transplantation, dynamically endothelialized scaECM-TEVGs remained patent for 6 weeks in a pig carotid interposition bypass model. When compared with nonrevitalized control grafts, reendothelialized grafts provided excellent antithrombogenic activity, inhibited intimal hyperplasia formation, and encouraged media wall infiltration and reorganization with recruited host SMCs. We thus demonstrate that readily available decellularized scaECM can be promptly revitalized with autologous cells in a 3-week period before implantation, indicating applicability as a future platform for vascular reconstructive procedures.

Dataset Information

Cell-assembled extracellular matrix (CAM) sheet production: Translation from using human to large animal cells.

Publications

Cell-assembled extracellular matrix (CAM) sheet production: Translation from using human to large animal cells.

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